The method of obtaining phenylpropionic acid

 

(57) Abstract:

Describes how to obtain phenylpropionic acid selected from 2-(4-isobutylphenyl)propionic or 2-(2-fluoro-4-biphenylyl)propionic acid or their salts, such as methylbenzylamine, or lysine, or sodium salt, which is enriched in the desired enantiomer, including phase separation, which is carried out by treatment of the corresponding racemic acid enantiomer-methylbenzylamine in the solvent by heating, with the formation of the corresponding salt phenylpropionic acid, which is enriched in the desired enantiomer and which is separated from the subsequent transformation into phenylpropionate acid or one of the above salts, enriched in the desired enantiomer, and the stage of recrystallization, characterized in that at the stage of separation (a) a mixture of solvents such as toluene and methanol, and it is carried out at a molar ratio essentially racemic, phenylpropionic acid to methylbenzylamino equal to 1:0.25 to 1:1, and then carry out the stage of recrystallization (C) where the resulting enriched salt is recrystallized from a mixture of methanol with toluene to obtain-methylbenzylamine salt phenylpropionic the July release (s), where phenylpropionate acid, which optionally enriched in the desired enantiomer, isolated from the recrystallized salt, (d) an optional step for salt, where solid salt phenylpropionic acid, optionally enriched in the desired enantiomer, allocate, and solid salt is optional even more enriched in the desired enantiomer. The technical result is simplification. 23 C.p. f-crystals, 2 tab. , 1 Il.

The invention relates to obtain essentially pure enantiomers phenylpropionic acids selected from ibuprofen, flurbiprofen and their pharmaceutically acceptable salts, in particular their methylbenzylamino, lysine and sodium salts.

Ibuprofen chemical name is 2-(4-isobutylphenyl) propionic acid, flurbiprofen, chemical name 2-(2-fluoro-4-biphenylyl)propionic acid, are well known drugs anti-inflammatory, antipyretic and analgesic actions. To well-known applications of ibuprofen and flurbiprofen include reduction of pain and inflammation in musculoskeletal disorders, such as rheumatism, and pain in a variety of other ailments, nuprime chiral center on the asymmetrically substituted carbon atom, and, therefore, they both exist in two enantiomeric forms. It is known that S(+)- ibuprofen is the active tool, and that in the body of R(-)-ibuprofen may not fully turn into S(+)-ibuprofen. It is also known that S(+)-flurbiprofen is the active tool. In humans, the R(-)-flurbiprofen is not converted into (S)-enantiomer, although there is an opinion that the analgesic effect has only R(-)-flurbiprofen (international patent application WO 92/04018 (Paz)). Ibuprofen and flurbiprofen did earlier in the sale in the form of racemic mixtures. However, in some cases it may be appropriate to introduce essentially only one enantiomer. Therefore, it is desirable to have improved methods of obtaining a product enriched in the desired enantiomer of phenylpropionic acid selected from ibuprofen and flurbiprofen.

In European patent application 0362476 (Paz) described the separation of enantiomeric forms arylpropionic acids by selective crystallization diastereoisomeric salt in a polar solvent. It is argued that the use of polar solvents is more favorable than non-polar, which is at odds with the use of specific mixtures rastvoritelyakh carboxylic acid, including ibuprofen and flurbiprofen, treatment of a solution of their salts of chiral organic basis for the selective precipitation of the less soluble diastereoisomer. No indication of the use of specific mixtures of solvents used in the way that meets the present invention.

In European patent application 0437369 described obtaining (S)-ibuprofen-(S)-lysine salt by contacting racemic ibuprofen with equimolar amounts of (S)-lysine in aqueous mixtures of organic solvents, separating any suspended solids from the mixture, cooling the transparent mixture to achieve a supersaturated condition with respect to both (R)-ibuprofen-(S)-lysine and (S)-ibuprofen-(S)-lysine salt, contacting the supersaturated solution with a slurry of (S)-ibuprofen-(S)-lysine salts and separation of the formed crystalline (S)-ibuprofen-(S)-lysine salt.

In international patent application WO 92/20334 (Boots) describes the obtaining of sodium salt of (S)-ibuprofen.

The present invention provides a method of obtaining a product enriched in the desired enantiomer of phenylpropionic acid selected from ibuprofen and flurbiprofen, including SEB is a new acid, which is enriched in the desired enantiomer by contacting a mixture of toluene and methanol, which plays the role of the solvent, essentially racemic mixture of phenylpropionic acid with an enantiomer - methylbenzylamine, and the corresponding molar ratio of the content is essentially the racemic phenylpropionic acid to methylbenzylamino is located in the region from about 1:0.25 and about 1:1,

b) stage of recrystallization, in which the resulting enriched salt is subjected to recrystallization from a mixture of methanol and toluene to obtain-methylbenzylamine salt phenylpropionic acid, which optionally enriched in the desired enantiomer,

(C) an optional step of selecting, on which phenylpropionate acid, which optionally enriched in the desired enantiomer, isolated from the recrystallized salt,

d) an optional step of obtaining salt, on which solid salt phenylpropionic acid, optionally enriched in the desired enantiomer, allocate, and solid salt can be that is not mandatory, even more enantiomeric enriched in the desired enantiomer.

In preferred embodiments of the method, the p and

a) at the first stage of separation is essentially racemizes phenylpropionate acid and (S)--methylbenzylamine used in the respective molar ratio, in the region from about 1:0.35 and about 1:0.8 to, for example, in the area from about 1:0.4 to about 1:0.6 to, and preparation takes place in a mixture of methanol with toluene, in which toluene is contained in an amount constituting at least about 50%, more preferably in amounts of about 60% and about 90%, and most preferably in amount of about 70% and about 80% of the total volume of the mixture, the temperature of the mixture is in the region of from about 30oC and approximately 70oC, preferably in the region from approximately 40oC and approximately 60oC to form a supersaturated solution from which (S)--methylbenzylamino Sol phenylpropionic acid enriched (S)-enantiomer of phenylpropionic acid, crystallized, for example, by cooling the solution to a temperature in the region from about -10oC and approximately 30oC, preferably in the region from approximately 0oC and up to about 5oC,

b) at the stage of recrystallization, the preferred solvent is the RNO 25%, more preferably in an amount constituting from about 50% to about 80%, and most preferably in amount of about 60% and about 70% of the total volume of the mixture of (S)--methylbenzylamino Sol phenylpropionic acid, optionally enriched (S)-enantiomer of phenylpropionic acid, crystallized, for example, by cooling the solution to a temperature in the region of from about -10oC and approximately 30oC, preferably in the region from approximately 0oC and up to about 5oC,

c) at the stage of selection (S)--methylbenzylamino Sol phenylpropionic acid, optionally enriched (S)-enantiomer and obtained at the stage of recrystallization, acidified (e.g., hydrochloric acid) in an immiscible with water, the solvent for the solution selected phenylpropionic acid enriched (S)-enantiomer, immiscible with water, the solvent and the aqueous solution (S)--methylbenzylamine salts (e.g. salts of hydrochloric acid), which can be selected (S)--methylbenzylamine, therefore it can be used again at a later stage splitting (a), for example, the alkalization of the solution extraction vysvobozhdeno what antiserum phenylpropionic acid immiscible with water, the solvent, obtained at the stage of selection (c), can be further processed by one or more of the following ways:

I) crystallization and separation of solid phenylpropionic acid enriched (S)-enantiomer, from the solution,

II) removing the solvent by distillation to obtain a melt, which can be used in stage (V) described below,

III) if phenylpropionate acid is a ibuprofen, then by contacting with an aqueous solution containing sodium base (e.g. sodium hydroxide) to obtain an aqueous solution of sodium salt of ibuprofen, which is separated from the immiscible with water solvent, and the aqueous solution is diluted with acetone for crystallization is additionally enriched (S)-enantiomer of sodium salt of ibuprofen, and

IV) if phenylpropionate acid is a ibuprofen, then contacts with (S)-lysine and water, in which the molar ratio of the concentrations of ibuprofen (S)-lysine is in the range from 1:0.5 to 1: 1, to obtain an aqueous solution (S)-lysine salt which is separated from the immiscible solvent, and then to the water solution add ethanol to the crystallization of (S)-lysine with the(III) may be used on one or more subsequent stages:

V) a solid substance with the above-described stage d(I), or the melt from step d(II), which is separated and subjected to interaction in aqueous ethanol solution with (S)-lysine, in which the molar ratio of the contents of phenylpropionic acid to (S)-lysine is in the range from 1:0.5 to 1:1, is used to obtain after crystallization and separation of (S)-lysine salt phenylpropionic acid, optionally enriched (S)-enantiomer,

VI) acidification additionally enriched (S)-enantiomer of sodium salt of ibuprofen with the above-described stage d(III) in the presence of immiscible with water solvent, such as heptane to obtain a solution enriched (S)-enantiomer of ibuprofen in immiscible with water, the solvent, which is separated. Solid enriched (S)-ibuprofen enantiomer is then crystallized and was isolated, and

VII) acidification of an aqueous solution enriched (S)-enantiomer of sodium salt of ibuprofen with the above step d(III) at elevated temperature (for example, at 60oC) a melt, which is separated from the aqueous layer and treated as described above in step (V).

In more preferred embodiments of the method, when the er - (S)-enantiomer. In this preferred embodiment,

a) phase separation receive (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity in the region of from about 80% to about 95% by weight and a first mother liquor containing enriched (R)-enantiomer of ibuprofen, which is used at the stage of racemization (e) to obtain essentially racemic ibuprofen, which is administered as part of the source material used in the next phase separation (a),

b) stage of recrystallization involves two stages:

I) the first stage of recrystallization, which includes the recrystallization step (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen obtained by splitting step (a), to obtain (S)-methylbenzylamine salt enriched (S)-enantiomer of ibuprofen preferably the enantiomeric purity in the region of from about 90 to about 99.9%, more preferably in the region from about 94 to about 99% by weight and the second mother liquor containing (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity from about 40 to about 70%, more preferably in the field about the next stage of division (a),

II) the second stage of recrystallization, which includes the recrystallization step (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen obtained in the first stage of recrystallization (b)(I), to obtain essentially enantiomerically pure (S)-ibuprofen-(S)-methylbenzylamine preferably the enantiomeric purity of about 99% and a third mother liquor containing (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity in the region of from about 85 and about 95% by weight, preferably in the region from about 88 to about 95% by weight, and a third mother liquor introduced as part of the solvent used at the next first stage of recrystallization (b)(I).

In the most preferred embodiment of the invention, the first mother liquor from the splitting step (a) is subjected to azeotropic distillation to remove essentially all of the methanol at the temperature at which essentially eliminates the formation of by-products, and the distillate is again used as part of a solvent, at a later stage separation (a). The residue remaining after the above-mentioned distillation, may be acidified, for example, hloristovodorodnykh and the organic phase, containing ibuprofen, enriched (R)-enantiomer. The aqueous solution is then separated and acidified to obtain the free (S)--methylbenzylamine, which is extracted with toluene and again used as an agent of separation at the initial stage of the next phase separation (a) along with (S)--methylbenzylamino retrieved on stage (stages) of the selection. The organic phase containing ibuprofen, enriched (R)-enantiomer, can be racemethionine on stage racemization (e) any known method for obtaining essentially racemic ibuprofen, which can then be introduced as part of the solvent used at the initial stage of the subsequent splitting step (a).

It is advisable that at each stage of the method conforming to the present invention, liquids, not containing phenylpropionate acid, preferably enriched with enantiomer has been recycled by using them in the previous stages of the method. The combination of phase separation (a) and phase recrystallization (b) phase racemization (e) and phase extracting agent separation -(S) - methylbenzylamine gives advantages by eliminating the need to handle numerous is ergie and raw materials.

Phase recrystallization in the way described above, may include, though not necessarily, the third and/or subsequent stage of recrystallization.

This preferred United way is illustrated by reference to the drawing, which shows a schematic process diagram of a preferred embodiment of the invention for obtaining (S)-ibuprofen, where the letters refer to the steps or stages that are marked by symbols (a), (b)(I) (b)(II), (c), (d) and (e) in the above-described methods, and the numbers 1 to 3 indicate the first or third mother liquor, respectively, the number 4 indicates recycled (S)--methylbenzylamine and number 5 on recycled racemethionine ibuprofen. In the drawing, dotted lines indicate recycled materials and solid lines - material, increasing the enrichment of (S)-ibuprofen in the direction shown by the arrow.

On the splitting step (a) receive the product (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen, which is used as source material in the first stage of recrystallization (b)(I). The first mother liquor from (I) splitting step (a) is served on the stage racemization (e), from which the title deed of separation (a), and lessons (S)--methylbenzylamine (4) is subjected to recycling for use as part of a separating agent for subsequent splitting step (a). The second uterine fluid (2) from the first stage of recrystallization (b)(II) is subjected to recycling for use at a later stage splitting (a). The product of the first stage of recrystallization (b)(I) process at the second stage of recrystallization (b)(II) to obtain (S)-ibuprofen-(S) - methylbenzylamine high enantiomeric purity and a third mother liquor, which has undergone recycling education part of the solvent used in the subsequent first phase recrystallization (b)(I). The product from the second stage of recrystallization (b)(II) is used then at the stage of selection (c) to obtain (S)-ibuprofen high enantiomeric purity. (S)--Methylbenzylamine (4), which also emit at the stage of selection (c), is subjected to recycling for use as part of a separating agent for subsequent splitting step (a). Freed (S)-ibuprofen may then be used in optional step of obtaining salt (d) to form salts (e.g. sodium salt or (S)-lysine) containing (S)-ibuprofen higher anandibai ibuprofen and the desired enantiomer is (S)-enantiomer, can be used for the preparation of (S)-lysine salt enriched (S)-enantiomer of ibuprofen by contacting the selected ibuprofen, enriched (S)-enantiomer, (S)-lysine, preferably with stoichiometric amounts or with a smaller number (S)-lysine for the formation of (S)-lysine salt of ibuprofen, additionally enriched (S)-enantiomer, and more preferably, the molar ratio of the concentrations of ibuprofen (S)-lysine has been in the area from about 1:0.5 and about 1:1, preferably in the region from about 1:0.5 and about 1:0.95 to. Selected ibuprofen, enriched (S)-enantiomer can also be brought into contact with sodium hydroxide to obtain enriched (S)-enantiomer of ibuprofen sodium (see for example, international patent application WO 92/20334).

In another preferred embodiment of the method conforming to the present invention, receive (S)-ibuprofen and its salts high enantiomeric purity.

Unexpectedly, it was also discovered that flurbiprofen, enriched (S)-enantiomer can be bicrystalline of toluene with the efficient removal of the other enantiomer and obtaining (S)-flurbiprofen high-flurbiprofen or their pharmaceutically acceptable salts described above can be easily adapted to obtain the R(-)-ibuprofen, R(-)-flurbiprofen or their pharmaceutically acceptable salts by the use of (R)--methylbenzylamine instead of (S)--methylbenzylamine as agent for the separation of the splitting step (a) methods that meet present invention, with appropriate modification of the subsequent stages.

The invention will be further illustrated by the following examples.

Example 1.

Separation of ibuprofen through the preparation of ibuprofen-(S) - methylbenzylamine enriched (S)-enantiomer (the splitting step (a)).

Recycled racemic ibuprofen (530 kg) was dissolved in toluene (1335 l), methanol (900 l) was added to the solution and the mixture was heated with stirring to 66oC. Recycled (S)--methylbenzylamine (247 kg) in toluene (200 l) was added over 3 hours while maintaining the temperature in the region of 65-70oC. the Mixture is finally cooled to a temperature in the range from 0 to 5oC under stirring, and stirred at this temperature for one hour. The desired product was collected by filtration, washed with toluene (600 l). Product contain (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric frequency 89,3% wasr 2.

Phase recrystallization (S) -- methylbenzylamine salt of ibuprofen, enriched (S)-enantiomer (phase recrystallization (b)).

Example 2(a) (the First stage of recrystallization (b)(I)).

(S)--Methylbenzylamine salt enriched (S)-enantiomer of ibuprofen (635 kg) with enantiomeric purity of 85.5% by weight, obtained by the method similar to those described above (example 1), toluene (598 l) and recyclebank second mother liquor (2350 l) obtained in the example below, B2 and contains (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen (214 kg) and methanol (800 l), stirred, heated and dissolved in 67oC, and then, finally, cooled to a temperature in the range from 0 to 5oC. the Resulting solid was collected by filtration. The product was represented by (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity 94,1% by weight.

Example 2(b) (the Second stage of recrystallization (b)(II)).

In a way similar to the one used in the first stage of recrystallization, as described above in example 2(a), (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity 91.4 per cent by weight (629 kg received ivali toluene, the result was achieved enantiomeric purity value of 98.5% by weight.

Examples 2(a) and 2(b) indicate that a significant increase in the enantiomeric purity of (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen can be achieved at the stage of recrystallization in a way that meets the present invention.

Example 3(a).

The selection of ibuprofen, enriched (S)-enantiomer, in toluene solution (stage selection (c)).

(S)--Methylbenzylamine salt enriched (S)-enantiomer of ibuprofen (485 kg of salt, prepared as described above in example 2 (b)), toluene (814 l), water (300 l) and concentrated hydrochloric acid with a density of 1.18 (170 kg) was stirred for 30 minutes and the Lower aqueous layer containing hydrochloric acid (S)--methylbenzylamine, separated, connected with a water liquids as described below in example 6, making it before recirculation is carried out so that as described above in example 1. The upper layer containing toluene solution of ibuprofen, enriched (S)-enantiomer, washed with water (100 l), resulting in a received 920 kg of a solution containing 300 kg of ibuprofen, enriched (S)-enantiomer, with an enantiomeric purity of 98.5% is profane, enriched (S)-enantiomer, with an enantiomeric purity of 98.2% (180 kg) in toluene (1221 kg) was washed with water. Water (220 l) and aqueous sodium hydroxide solution (47 l with a density of 1.5) was added, and the mixture was heated to 60oC and left to precipitate at 4 o'clock the Lower aqueous layer was separated and the toluene layer was washed with water. Water wash solution was combined with the aqueous layer. The residual toluene was removed by distillation and was added heptane (250 l) and concentrated hydrochloric acid (78 kg with a density of 1.18). Heptane layer was separated, washed with water and cooled to -10oC. Ibuprofen, enriched (S)-enantiomer, with an enantiomeric purity higher than 99% was collected by filtration and dried in vacuum. (Output amounted to 166 kg).

Example 4(a).

Obtain (S)-lysine salt enriched (S)-enantiomer of ibuprofen (the stage of obtaining the salt (d)).

Examples 4.1 to 4.12 conducted as described below with reference to the table. 1. Ibuprofen, enriched (S)-enantiomer (100 g of material containing "a"% (S)-enantiomer), was dissolved in ethanol (900 ml) at ambient temperature. Prepared solution monohydrate (S)-lysine ("b" g) in a mixture of water (c ml) and ethanol (d ml). The solution of ibuprofen and a solution of (S)-lysine was added in equimolar with the water (11 ml) and ethanol (125 ml) which was stirred at 20oC for 10 minutes the Mixture then was cooled to 0oC for one hour and then cooled to -10oC. the Mixture was stirred at -10oC for two hours. The resulting solid was collected by filtration, washed with ethyl acetate and dried in vacuum at 35oC, resulting in an (S)-lysine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity "e"% by weight.

Examples 4.1 through 4.12 show that at the stage of preparation by the method that meets the present invention can be achieved a significant increase in the enantiomeric purity of the (S)-lysine salt of ibuprofen, enriched (S)-enantiomer.

Example 4(b).

Obtain (S)-lysine salt of ibuprofen, enriched (S)-enantiomer (the stage of obtaining the salt (d)).

The solution enriched (S)-enantiomer of ibuprofen (30 g) in toluene (20 g) was heated at a temperature in the range from 60 to 70oC with (S)-lysine (40 g of 50% by weight aqueous solution) and water (20 ml). The lower aqueous layer was separated, and the residual solvent was removed by distillation. Added ethanol (460 ml) and the mixture was heated to 50 - 55oC and then cooled to a temperature in the range of 0oC to -10oC in quiescent what cetecom (50 ml) and dried in vacuum.

Example 5.

Preparation of sodium salt of ibuprofen, enriched (S)-enantiomer (the stage of obtaining the salt (d)).

The solution enriched (S)-enantiomer of ibuprofen with enantiomeric purity 95.5% of (211 kg) in toluene (797 kg) was heated to 60oC with water (300 l) and an aqueous solution of sodium hydroxide (52 l, a density of 1.5), and the mixture was left for 4 h for stratification. The aqueous layer was separated and the toluene layer was washed with water. Water washing and the aqueous layer were combined, and the residual toluene was removed by distillation. Acetone was added (1684 kg), and the mixture was cooled to 20oC. the Precipitated sodium salt dihydrate enriched (S)-enantiomer of ibuprofen (enantiomeric purity of 99.9%) was collected by filtration and dried in vacuum. (The output was 143,5 kg).

Example 6.

Processing the first mother liquor from stage separation.

The mixture of the first mother liquor from stage separation was concentrated by distillation to remove methanol and toluene to extract and re-use. Was added water (300 l) and concentrated hydrochloric acid (170 kg with a density of 1.18), and the mixture was stirred. The aqueous layer containing hydrochloric acid (S)--methylbenzylamine, separated and connected with a water rasam sodium hydroxide (340 l with a density of 1.5). Was added toluene (500 l), and the resulting solution (S)--methylbenzylamine used at a later stage separation, was treated according to a method similar to that described in example 1.

Methanol (300 l) and concentrated sulfuric acid was heated in a vessel under reflux for 2 h, the Upper organic layer was separated and heated in a vessel under reflux with methanol (75 l) and concentrated sulfuric acid (15 l) for 2 h, the Upper layer was separated and heated with solid sodium hydroxide (175 kg). The methanol was removed by distillation, and the residue was acidified with a mixture of concentrated hydrochloric acid (353 kg) and water (1750 l). The upper toluene layer containing racemic ibuprofen, washed with water and used on the phase separation during subsequent cooking, doing so, as described in example 1.

Example 7.

Division of flurbiprofen preparation of (S)--methylbenzylamine salt enriched (S)-enantiomer of flurbiprofen.

Racemic flurbiprofen (61,0 g) was dissolved in a mixture of methanol (40 ml) and toluene (160 ml). The mixture was heated to 60oC and for 10 min was added (S)--methylbenzylamine in the amount of 16.9 ml To the reaction mixture was added to bare C and kept at this temperature for one hour. The precipitate was collected by filtration, resulting in received (S)--methylbenzylamine salt enriched (S)-enantiomer of flurbiprofen with enantiomeric purity of 92.2%. After recrystallization of the precipitate from a mixture of methanol (48 ml) and toluene (192 ml) was obtained (S) -- methylbenzylamine salt enriched (S)-enantiomer of flurbiprofen with enantiomeric purity of 98.5%.

The mother liquid obtained by recrystallization, acidified with concentrated HCl (10 ml) with water (25 ml) and stirred at 25oC for 15 minutes Lower aqueous layer containing (S) - methylbenzylamine, collected and re-used. The upper organic layer contained a mixture of the enantiomers flurbiprofen acid, present in a weight ratio of 41.5:50.5% of S(+)-enantiomer R - (-)-enantiomer, respectively). This flurbiprofen was converted into its methyl ester, which was ratemyserver, turned back in racemic flurbiprofen sodium hydroxide and re-filed on the above described phase separation.

Example 8

Preparation of (R)-flurbiprofen-(R) - methylbenzylamine

The following examples from 8.1 to 8.6 conducted according to the table. 2. Racemic flurbiprofen in the amount of (I) g was dissolved the P>C to form a solution, and for 10 min was injected (V) ml (R)--methylbenzylamine. The seed crystal of (R)-flurbiprofen-(R) - methylbenzylamine was added to the mixture, which was cooled to 25oC. the Precipitate was collected by filtration, resulting in the received (R)--methylbenzylamine salt enriched (R)-enantiomer of flurbiprofen with enantiomeric purity (VI)%. After recrystallization of the precipitate from a mixture of methanol, toluene and water in the same proportion as the use of phase separation, received a solid representing the enriched (R)-enantiomer (R)-flurbiprofen-(R)--methylbenzylamine with enantiomeric purity (VII)%.

Example 9(a).

The selection of flurbiprofen enriched (R)-enantiomer.

(R)--Methylbenzylamine salt enriched R-enantiomer of flurbiprofen (58,7 g, was obtained in the same manner as described in example 8) with enantiomeric purity of 99.1%, was heated at 80oC for 15 min with a mixture of n-heptane (160 ml), water (200 ml) and concentrated hydrochloric acid (17 ml with a density of 1.18). The organic layer was separated and cooled to a temperature in the range from 0 to 5oC. Bicrystalline flurbiprofen, enriched (R)-enantiomer, enriched (S)-enantiomer.

By the way, is similar to that described in example 9 (a), was isolated flurbiprofen, enriched (S)-enantiomer, (S)--methylbenzylamine salt enriched (S)-enantiomer of flurbiprofen prepared according to the method similar to that described in example 7.

Example 10(a).

Enantiomeric purification of flurbiprofen enriched (S)-enantiomer, carrying out recrystallization.

Flurbiprofen, enriched (S)-enantiomer (47,2 g), enantiomeric purity 98.9 per cent, was added to toluene (132 ml) and heated to 50oC. was Added crystals of (S)-flurbiprofen with the temperature of the 42oC, and the solution was cooled to -5oC. Solid flurbiprofen, enriched (S)-enantiomer was collected by filtration and found that the enantiomeric purity is 99.9%.

Example 10(b).

Enantiomeric purification of flurbiprofen enriched (S)-enantiomer, carrying out recrystallization.

Flurbiprofen, enriched (S)-enantiomer (13.5 g) with enantiomeric purity 98.4 per cent, was added to toluene (26 ml) and heated to 50oC. the Solution is then cooled to -10oC. Solid flurbiprofen, enriched (S)-enantiomer was collected by filtration and found that enantiomeres of 2-(4-isobutylphenyl)propionic or 2-(2-fluoro-4-biphenylyl)propionic acid or their salts, such as methylbenzylamine, or lysine, or sodium salt, which is enriched in the desired enantiomer, including phase separation, which is carried out by treatment of the corresponding racemic acid enantiomer-methylbenzylamine in the solvent by heating, with the formation of the corresponding salt phenylpropionic acid, which is enriched in the desired enantiomer and which is separated from the subsequent transformation into phenylpropionate acid or one of the above salts, enriched in the desired enantiomer, and the stage of recrystallization, characterized in that at the stage of separation (a) a mixture of solvents such as toluene and methanol, and it is carried out at a molar ratio essentially racemic, phenylpropionic acid to methylbenzylamino equal to 1 : 0.25 to 1 : 1, and then carry out the stage of recrystallization (C) where the resulting enriched salt is recrystallized from a mixture of methanol with toluene to obtain-methylbenzylamine salt phenylpropionic acid, which optionally enriched in the desired enantiomer, followed by an optional stage of the release (s) on which phenylpropionate acid, which is additionally enriched required EN rdwy Sol phenylpropionic acid, additionally enriched in the desired enantiomer, allocate, and solid salt is optional even more enriched in the desired enantiomer.

2. The method according to p. 1, characterized in that the desired enantiomer of phenylpropionic acid selected from (S)-ibuprofen, (S)-flurbiprofen and (R)-flurbiprofen.

3. The method according to p. 1, characterized in that the desired enantiomer of phenylpropionic acid is a (S)-enantiomer and under division (a) of racemic phenylpropionate acid and (S)--methylbenzylamine used in a molar ratio in the range of about 1 : 0.35 to 1 : 0.8, the as solvent a mixture of methanol with toluene, in which the content of toluene is at least about 50% of the total volume of the mixture, the temperature of the mixture is kept in the range of about 30 - 70oWith the formation of a supersaturated solution from which vykristallizovyvalas (S)--methylbenzylamino Sol phenylpropionic acid enriched (S)-enantiomer, at the stage of recrystallization (C) the solvent is a mixture of methanol with toluene, in which the content of toluene is at least about 25% of the total mixture, from which vykristallizovyvalas (S)--methylbenzeneethanamine salt enriched (S)-enantiomer of phenylpropionic acid, obtained at the stage of recrystallization, acidified with in immiscible with water the solvent to obtain a solution free of enriched (S)-enantiomer of phenylpropionic acid immiscible with water solvent and an aqueous solution of salt (S)--methylbenzylamine, which can be released (S)--methylbenzylamine, which can be re-used under division (a).

4. The method according to p. 3, characterized in that the solution further enriched (S)-enantiomer of phenylpropionic acid immiscible with water, the solvent obtained at the stage of release (s) may be subjected to additional processing one or more of the following methods: d I/ crystallization and separation of the solid, phenylpropionic acid enriched (S)-enantiomer of solution d III/ if phenylpropionate acid is a ibuprofen, a method of contacting with an aqueous solution of sodium base to obtain an aqueous solution of nitrilebutadiene, which is separated from the immiscible with water solvent, moreover, in this case, the aqueous solution is diluted with acetone to crystallize sodium ibuprofen, additionally enriched (S)-enantiomer, or d IV/ if phenylpropionate is its molar ratio of ibuprofen to (S)-lysine is in the range of 1 : 0.5 to 1 : 1, to obtain an aqueous solution (S)-lysine salt which is separated from the immiscible solvent, followed by adding ethanol to the aqueous solution for crystallization of (S)-lysine salt of ibuprofen, additionally enriched (S)-enantiomer.

5. The method according to any of paragraphs.1 to 4, characterized in that the molar ratio essentially racemic, phenylpropionic acid to methylbenzylamino used under division (a) is in the range of 1 : 0.4 to 1 : 0.6 to.

6. The method according to any of paragraphs.1 to 5, characterized in that the mixture of methanol with toluene, used under division (a) contains about 60 to 90% toluene by volume of the total mixture.

7. The method according to p. 6, characterized in that the mixture used under division (a) contains about 70 - 80% toluene by volume of the total mixture.

8. The method according to any of paragraphs.1 to 7, characterized in that the initial temperature of the mixture used in this separation stage (a) is in the range of about 40 - 60oC.

9. The method according to any of paragraphs.1 to 8, characterized in that the mixture under division (a) is cooled to a temperature in the range of about (-10) - (+30)oC.

10. The method according to p. 9, distinguish the oC.

11. The method according to any of paragraphs.1 to 10, characterized in that the mixture used at the stage of recrystallization (), contains about 50 - 80% toluene by volume of the total mixture.

12. The method according to p. 11, characterized in that the mixture used at the stage of recrystallization (), contains about 60 - 70% toluene by volume of the total mixture.

13. The method according to any of paragraphs.1 - 12, characterized in that the solution at the stage of recrystallization () is cooled to a temperature in the range of about (-10) - (+30)oC.

14. The method according to p. 13, characterized in that the solution at the stage of recrystallization () is cooled to a temperature in the range of about 0 to 5oC.

15. The method according to any of paragraphs.1 to 14, characterized in that at the stage of selection (s) salt enriched (S)-enantiomer of phenylpropionic acid, obtained at the stage of recrystallization (), acidified with hydrochloric acid to obtain an aqueous solution of hydrochloric acid (S) - methylbenzylamine, which is alkalinized, and the base, passing into toluene, and the toluene extract is used again in the stage of separation (a).

16. The method according to p. 4 or any one of paragraphs.5 - 15, if he additional the e substance from the preparation stage acid d (I) is separated and subjected to interaction in aqueous ethanol solution with (S)-lysine, where appropriate molar ratio of phenylpropionic acid to (S)-lysine is in the range of about 1 : 0.5 to 1 : 1 to obtain after crystallization and separation of (S)-lysine salt, enriched (S)-enantiomer.

17. The method according to any of paragraphs.1 to 16, characterized in that phenylpropionate acid is a ibuprofen, the desired enantiomer is (S)-enantiomer and the separation stage (s) give (S)--methylbenzylamine salt enantiomeric purity in the range of about 80 to 95% by weight and a first mother liquor, which is used to produce racemic ibuprofen, which is injected in the form of the source material used under division (a), phase recrystallization (C) includes two stages: (bi) the first stage of recrystallization, including recrystallization (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen obtained under division (a), with (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen, preferably with enantiomeric purity in the range of about 90 to 99.9% by weight, and the second mother liquor containing (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofens solvent, used under division (a); (BII) the second stage of recrystallization, including recrystallization (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen obtained in the first stage of recrystallization (bi), to obtain essentially enantiomerically pure (S)-ibuprofen-(S) - methylbenzylamine preferably the enantiomeric purity of about 99% and a third mother liquor containing (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity in the range of approximately 85 to 95% by weight, and a third mother liquor introduced as part of the solvent used in the first stage of recrystallization (bi).

18. The method according to p. 17, characterized in that the enantiomeric purity of (S)-methylbenzylamine salt enriched (S)-enantiomer of ibuprofen obtained at the first stage of recrystallization (bi) is in the range of about 94 to 99% by weight.

19. The method according to any of the p. 17 and 18, characterized in that the second mother liquor contains (S)--methylbenzylamine salt enriched (S)-enantiomer of ibuprofen with enantiomeric purity in the range of about 40 to 60% by weight.

20. The method according to any of paragraphs.17 to 19, characterized in that the third me a purity in the range of about 88 - 95% by weight.

21. The method according to any of paragraphs.1 to 20, characterized in that the first mother liquor from stage separation (a) is subjected to azeotropic distillation to remove essentially all of the methanol at the temperature at which essentially eliminates the formation of by-products, and the distillate is again used as part of the solvent used under division (a).

22. The method according to p. 21, characterized in that the residue remaining from the distillation of the first mother liquor, acidified with formation of an aqueous solution of (S)--methylbenzylamine salt and the organic phase containing enriched (R)-ibuprofen enantiomer, and the aqueous solution is separated and alkalinized to get free (S)--methylbenzylamine, which is extracted with toluene and again used as an agent of separation at the initial stage of separation (a), along with (S)--methylbenzylamino extracted at the stage of separation, while the organic phase containing enriched (R)-enantiomer of ibuprofen, racemizing obtaining essentially racemic ibuprofen, which is then injected as part of the solvent used at the initial stage of separation (a).

23. The method according to p. 22, characterized t is noteslog (S)--methylbenzylamine.

24. The method according to any of paragraphs.1 to 23, characterized in that the stage of recrystallization (in) contains three or more stages of recrystallization.

 

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